Genetic Variants in Toll-Like Receptor 2 (TLR2), TLR4, TLR9, and FCγ Receptor II Are Associated with Antibody Response to Quadrivalent Meningococcal Conjugate Vaccine in HIV-Infected Youth

This study examined the association of host genetic variants with the antibody response to the quadrivalent meningococcal conjugate vaccine (MCV4) in HIV-infected youth. Genetic variants associated with severity of meningococcal disease, including the IgG Fc receptor (FCγRII)-A484T, interleukin-10 (IL-10)-A1082G, -C819T, and -C627A, IL-4-C589T, mannose binding lectin-2 (MBL2)-A/O, -H/L, -P/Q, and -X/Y, toll-like receptor 2 (TLR2)-G2408A, TLR4-A12874G and -C13174T, and TLR9-T1237C and -T1486C were determined by real-time PCR (RT-PCR) for 271 HIV-infected subjects (median, 17 years). Response was defined as a ≥4-fold increase from entry in bactericidal antibody titers to each serogroup. Generalized estimating equation (GEE) models were used to evaluate the association of allelic variants with the immunologic response to all serogroups within each subject with and without adjusting for CD4 percentage and HIV viral load. At week 4, but not after, subjects with TLR2-2408-G/A versus -G/G genotypes and the TLR4-12874-A/A genotype were more likely to achieve a ≥4-fold increase overall in the four serogroups (unadjusted P of 0.006 and adjusted P of 0.008 and unadjusted P of 0.008 and adjusted P of 0.019, respectively). At week 28, the TLR9-1237 T allele was associated with enhanced antibody response (T allele versus C/C, unadjusted P of 0.014 and adjusted P of 0.009), which was maintained at week 72 (unadjusted and adjusted P of 0.008). At week 72, the FcγRII-131Arg allotype was associated with a ≥4-fold increase in antibody titer versus those with His/His (unadjusted P of 0.009; adjusted P of <0.001). These findings suggest that for HIV-infected youth, the initial antibody response to MCV4 is associated with variants in TLR2 and TLR4 while the long-term response is associated with genetic polymorphisms in TLR9 and FcγRIIa.     

Exenatide and sitagliptin are not associated with increased risk of acute renal failure: a retrospective claims analysis

Aim: This study evaluated whether the risk of acute renal failure (ARF) increases with exenatide and sitagliptin use. Methods: A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 4 91 539 patients were analysed. Cox proportional hazard models were used to compare the risk of ARF between diabetic and non‐diabetic subjects and between diabetic patients treated with exenatide, sitagliptin and control medications. Results: Adjusted Cox analyses showed diabetic subjects had a higher risk of ARF [HR 1.51, confidence interval (CI) 1.26–1.81, p < 0.001] than non‐diabetic controls. Compared with diabetic controls, neither exenatide (HR 0.77, CI 0.42–1.41, p = 0.40) nor sitagliptin (HR 1.17, CI 0.82–1.65, p = 0.39) increased the risk of ARF. Conclusion: Our study revealed an increased incidence of ARF in diabetic versus non‐diabetic patients but no association between use of exenatide or sitagliptin and ARF. Because of the limitations of this observational analysis, we cannot exclude the possibility of a very small increased risk.     

Phosphorylation of rat aquaporin‐4 at Ser111 is not required for channel gating

Aquaporin 4 (AQP4) is the predominant water channel in the mammalian brain and is mainly expressed in the perivascular glial endfeet at the brain‐blood interface. AQP4 has been described as an important entry and exit site for water during formation of brain edema and regulation of AQP4 is therefore of therapeutic interest. Phosphorylation of some aquaporins has been proposed to regulate their water permeability via gating of the channel itself. Protein kinase (PK)‐dependent phosphorylation of Ser¹¹¹ has been reported to increase the water permeability of AQP4 expressed in an astrocytic cell line. This possibility was, however, questioned based on the crystal structure of the human AQP4. Our study aimed to resolve if Ser¹¹¹ was indeed a site involved in phosphorylation‐mediated gating of AQP4. The water permeability of AQP4‐expressing Xenopus oocytes was not altered by a range of activators and inhibitors of PKG and PKA. Mutation of Ser¹¹¹ to alanine or aspartate (to prevent or mimic phosphorylation) did not change the water permeability of AQP4. PKG activation had no effect on the water permeability of AQP4 in primary cultures of rat astrocytes. Molecular dynamics simulations of a phosphorylation of AQP4.Ser¹¹¹ recorded no phosphorylation‐induced change in water permeability. A phospho‐specific antibody, exclusively recognizing AQP4 when phosphorylated on Ser¹¹¹, failed to detect phosphorylation in cell lysate of rat brain stimulated by conditions proposed to induce phosphorylation of this residue. Thus, our data indicate a lack of phosphorylation of Ser¹¹¹ and of phosphorylation‐dependent gating of AQP4.